Wet granulation formulation for bisphosphonic acids

ABSTRACT

Pharmaceutical compositions of bisphosphonic acids, and salts thereof, are prepared by wet granulation tablet formulation. These pharmaceutical compositions are useful in the treatment of disturbances involving calcium or phosphate metabolism, in particular, the treatment and prevention of diseases involving bone resorption, especially osteoporosis, Paget&#39;s disease, malignant hypercalcemia, and metastatic bone disease. These compositions are prepared without the addition of binder; instead, the drug itself acts as a binder.

BACKGROUND OF THE INVENTION

[0001] The pharmaceutical industry employs various methods forcompounding pharmaceutical agents in tablet formulations. In particular,wet granulation is one of the most prevalent methods. Tablets preparedby wet granulation generally require the addition of a binding agent tokeep the tablet together.

[0002] A variety of bisphosphonic acids have been disclosed as beinguseful in the treatment and prevention of diseases involving boneresorption. Representative examples may be found in the following: U.S.Pat. Nos. 3,962,432; 4,054,598; 4,267,108; 4,327,039; 4,621,077;4,624,947; 4,746,654; 4,922;077; and EPO Patent Pub. No. 0,252,504.Standard methods for tablet formulation of bisphosphonic acids, however,suffer difficulties.

[0003] Wet granulated formulations need to have an agent called a“binder,” which, in contact with water, swells or starts dissolving,forming a gel-like consistency. Traditionally, starch, starch paste,gelatin, and cellulosics such as hydroxypropylmethyl cellulose,hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidoneare used as binding agents in wet granulation formulations. (See,Remington's Pharmaceutical Sciences, 18th ed, (Mack Publishing Company:Easton, Pa., 1990), pp.1635-36). Microcrystalline cellulose, such asAvicel PH101, may be employed as a binder or compression aid incompositions prepared by dry granulation formulation, butmicrocrystalline cellulose functions primarily as a bulking agent in wetgranulation formulations because the microcrystalline cellulose losesmuch of its binding properties upon wetting.

[0004] The wet granulation process helps to form agglomerates ofpowders. These agglomerates are called “granules.” The present inventionprovides for a wet granulated formulation of bisphosphonic acids andprocess therefor wherein the tablet formulation does not contain anybinder. Instead, the drug itself acts as a binder. The absence of aseparate binder keeps the formulation simpler, and minimizes adverseeffects that binding agents can have on dissolution. Elimination ofbinder also simplifies the optimization and characterization of theformulation.

DESCRIPTION OF THE INVENTION

[0005] The present invention is directed in a first embodiment to aprocess for the preparation of pharmaceutical compositions ofbisphosphonic acids by wet granulation formulation. This process employsa blend of a bisphosphonic acid and minimal amounts of other processingaids with no binder added. This tablet formulation is prepared by:

[0006] (1) forming a powder blend of the active ingredient withdiluents,

[0007] (2) wet granulating the powder blend with water to form granules,

[0008] (3) drying the granules to remove water, and

[0009] (4) compressing the lubricated granule mixture into a desiredtablet form.

[0010] The shape of the tablet is not critical.

[0011] More specifically, this embodiment of the present inventionconcerns a process for the preparation of a tablet containing abisphosphonic acid as an active ingredient which process comprises:

[0012] (1) forming a powder blend of the active ingredient with diluentsfrom 3 to 25 minutes using a mixer such as a planetary or high sheargranulator,

[0013] (2) wet granulating the powder blend by the addition of waterwhile mixing over a 2 to 30 minute period to form granules,

[0014] (3) drying the granules to remove water by the use of heated airfor 10 minutes to 24 hours in a dryer (fluid bed or tray type),

[0015] (4) milling the dried granules to a uniform size,

[0016] (5) adding and blending a disintegrant with the dried milledparticles for 2 to 30 minutes,

[0017] (6) adding and blending a lubricant to the mixture containing thedisintegrant for 30 seconds to 20 minutes, and

[0018] (7) compressing the lubricated granule mixture into a desiredtablet form.

[0019] One particularly preferred process employs a high sheargranulator as a mixer and comprises the steps of:

[0020] (1) forming a powder blend of4-amino-1-hydroxybutylidene-1,1-bisphosphornic acid, microcrystallinecellulose, such as Avicel PH101, and lactose with a high sheargranulator for 3 to 5 minutes,

[0021] (2) wet granulating the powder blend by the addition of waterwhile mixing over a 3 to 5 minute period to form granules with the highshear granulator,

[0022] (3) drying the granules to remove water by the use of heated airby drying 10 minutes to 1 hour with a fluid bed, or 12-24 hours in atray dryer, preferably with a fluid bed,

[0023] (4) milling the dried granules to a uniform size using a hammertype mill,

[0024] (5) adding and blending the disintegrant croscarmellose sodium NFtype A with the dried milled particles for 3 to 8 minutes,

[0025] (6) adding and blending magnesium stearate lubricant to themixture containing the croscarmellose sodium NF type A disintegrant witha ribbon blender or a planetary mixer for 3 to 8 minutes, and

[0026] (7) compressing the lubricated granule mixture into a desiredtablet form, and

[0027] (8) dedusting and storing the tablets.

[0028] Another particularly preferred process employs a planetarygranulator as a mixer and comprises the steps of:

[0029] (1) forming a powder blend of4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, microcrystallinecellulose such as Avicel PH101, and lactose with a planetary granulatorfor 10 to 25 minutes,

[0030] (2) wet granulating the powder blend by the addition of waterwhile mixing over a 3 to 10 minute period to form granules with theplanetary granulator,

[0031] (3) drying the granules to remove water by the use of heated airby drying 10 minutes to 1 hour with a fluid bed, or 12-24 hours in atray dryer, preferably with a fluid bed,

[0032] (4) milling the dried granules to a uniform size using a hammertype mill,

[0033] (5) adding and blending the disintegrant croscarmellose sodium NFtype A with the dried milled particles for 3 to 8 minutes,

[0034] (6) adding and blending magnesium stearate lubricant to themixture containing the croscarmellose sodium NF type A disintegrant witha ribbon blender or a planetary granulator for 3 to 8 minutes, and

[0035] (7) compressing the lubricated granule mixture into a desiredtablet form, and

[0036] (8) dedusting and storing the tablets.

[0037] Still another particularly preferred process employs a high sheargranulator as mixer, and comprises the steps of:

[0038] (1) forming a powder blend of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, microcrystalline cellulose, such as Avicel PH101,and lactose with a high shear granulator for 3 to 5 minutes,

[0039] (2) wet granulating the powder blend by the addition of waterwhile mixing over a 3 to 5 minute period to form granules with a highshear granulator,

[0040] (3) drying the granules to remove water by the use of heated airfor 10 minutes to one hour using a fluid bed dryer,

[0041] (4) milling the dried granules to a uniform size using a hammertype mill,

[0042] (5) adding and blending the disintegrant croscarmellose sodium NFtype A with the dried milled particles for 3 to 8 minutes,

[0043] (6) adding and blending magnesium stearate lubricant to themixture containing the croscarmellose sodium NF type A disintegrant witha ribbon blender for 3 to 8 minutes,

[0044] (7) compressing the lubricated granule mixture into a desiredtablet form, and

[0045] (8) dedusting and storing the tablets.

[0046] Granulation is the process of adding water to a powder mixturewith mixing until granules are formed. The granulation step may bevaried from 2 to 30 minutes, preferably 2 to 5 minutes. The lubricationstep is the process of adding lubricant to the mixture; the lubricationstep may be varied from 30 seconds to 20 minutes, preferably 3 to 8minutes.

[0047] The disclosed process may be used to prepare solid dosage forms,particularly tablets, for medicinal administration.

[0048] Preferred diluents include: lactose, microcrystalline cellulose,calcium phosphate(s), mannitol, powdered cellulose, pregelatinizedstarch, and other suitable diluents. Especially preferred are lactoseand microcrystalline cellulose. In particular, microcrystallionecellulose NF, especially Avicel PH101, the trademarked name formicrocrystalline cellulose NF manufactured by FMC Corp. is preferred.

[0049] The disintegrant may be one of several modified starches ormodified cellulose polymers, in particular, croscarmellose sodium ispreferred. Croscarmellose sodium NF Type A is commercially availableunder the trade name “Ac-di-sol”.

[0050] Preferred lubricants include magnesium stearate, calciumstearate, stearic acid, surface active agents such as sodium laurylsulfate, propylene glycol, sodium dodecane sulfonate, sodium oleatesulfonate, and sodium laurate mixed with stearates and talc, sodiumstearyl fumerate, and other known lubricants. Especially preferred ismagnesium stearate.

[0051] Examples of the bisphosphonic acids which may be employed asactive ingredients in the instant invention include:

[0052] (a) 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;

[0053] (b) N-methyl-4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;

[0054] (c) 4-(N,N-dimethylamino)-1-hydroxybutylidene-1,1-bisphosphonicacid;

[0055] (d) 3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid;

[0056] (e) 3-(N,N-dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonicacid;

[0057] (f)1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid;

[0058] (g) 1-hydroxy-2-[3-pyridyl]ethylidene-1,1-bisphosphonic acid; and

[0059] (h) 4-(hydroxymethylene-1,1-bisphosphonic acid) -piperidine;

[0060] or pharmaceutically acceptable salts thereof.

[0061] Methods for the preparation of bisphosphonic acids may be foundin, e.g., U.S. Pat. Nos. 3,962,432; 4,054,598; 4,267,108; 4,327,039;4,407,761; 4,621,077; 4,624,947; 4,746,654; 4,922,077; and EPO PatentPub. No. 0,252,504. In particular, methods for the preparation of4-amino-1-hydroxy-butylidene-1,1-bisphosphonic acid and4-amino-1-hydroxy-butylidene-1,1-bisphosphonic acid monosodium salttrihydrate may be found in U.S. Pat. Nos. 4,407,761 and 4,922,077,respectively.

[0062] The pharmaceutically acceptable salts of bisphosphonic acids mayalso be employed in the instant invention. Examples of base salts ofbisphosphonic acids include ammonium salts, alkali metal salts such aspotassium and sodium (including mono-, di- and tri-sodium) salts (whichare preferred), alkaline earth metal salts such as calcium and magnesiumsalts, salts with organic bases such as dicyclohexylamine salts,N-methyl-D-glucamine, and salts with amino acids such as arginine,lysine, and so forth. The non-toxic, physiologically acceptable saltsare preferred. The salts may be prepared by methods known in the art,such as in U.S. Pat. No. 4,922,077.

[0063] In the present invention it is preferred that the bisphosphonicacid is 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid. It is evenmore preferred that the bisphosphonic acid is a sodium salt of4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, in particular,4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium salttrihydrate.

[0064] Preferred pharmaceutical compositions comprise about 0.5 to 40%by weight of a bisphosphonic acid as an active ingredient; about 10 to80% by weight of anhydrous lactose or hydrous fast flow lactose; about 5to 50% by weight of microcrystalline cellulose; and about 0.1 to 5% byweight of magnesium stearate.

[0065] The preferred pharmaceutical compositions are generally in theform of tablets. The tablets may be, for example, from 50 mg to 1.0 g innet weight, more preferably 100 to 500 mg net weight, and even morepreferably 150 to 300 mg net weight.

[0066] More preferred pharmaceutical compositions in accordance with thepresent invention comprise: about 0.5 to 25% by weight of abisphosphonic acid selected from4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid and4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium salttrihydrate; about 30 to 70% by weight of anhydrous lactose or hydrousfast flow lactose; about 30 to 50% by weight of microcrystallinecellulose; about 0.1 to 2% by weight of magnesium stearate; and about0.5 to 2% by weight of a disintegrant such as croscarmellose sodium.

[0067] Especially preferred pharmaceutical compositions comprise about 1to 25% of the active ingredient, about 40 to 60% by weight of anhydrouslactose; about 35 to 45% by weight of microcrystalline cellulose; about0.5 to 2% by weight of croscarmellose sodium; and about 0.1 to 1% byweight of magnesium stearate. Preferred pharmaceutical compositions asenvisioned for commercial development are as follows.

[0068] Tablets of 2.5 mg potency free acid:

[0069] about 1.63% by weight of4-amino-1-hydroxy-butylidene-1,1-bisphosphonic acid monosodium salttrihydrate; about 56.87% by weight of anhydrous lactose; about 40% byweight of microcrystalline cellulose; about 1% by weight ofcroscarmellose sodium; and about 0.5% by weight of magnesium stearate.

[0070] Tablets of 5 mg potency free acid:

[0071] about 3.25% by weight of4-amino-1-hydroxy-butylidene-1,1-bisphosphonic acid monosodium salttrihydrate; about 55.25% by weight of anhydrous lactose; about 40% byweight of microcrystalline cellulose; about 1% by weight ofcroscarmellose sodium; and about 0.5% by weight of magnesium stearate.

[0072] Tablets of 10 mg potency free acid:

[0073] about 6.5% by weight of4-amino-1-hydroxy-butylidene-1,1-bisphosphonic acid monosodium salttrihydrate; about 52.0% by weight of anhydrous lactose; about 40% byweight of microcrystalline cellulose; about 1% by weight ofcroscarmellose sodium; and about 0.5% by weight of magnesium stearate.

[0074] Tablets of 20 mg potency free acid:

[0075] about 13.0% by weight of4-amino-1-hydroxy-butylidene-1,1-bisphosphonic acid monosodium salttrihydrate; about 45.5% by weight of anhydrous lactose; about 40% byweight of microcrystalline cellulose; about 1% by weight ofcroscarmellose sodium; and about 0.5% by weight of magnesium stearate.

[0076] Tablets of 40 mg potency free acid:

[0077] about 26.0% by weight of4-amino-1-hydroxy-butylidene-1,1-bisphosphonic acid monosodium salttrihydrate; about 32.5% by weight of anhydrous lactose; about 40% byweight of microcrystalline cellulose; about 1% by weight ofcroscarmellose sodium; and about 0.5% by weight of magnesium stearate.

[0078] Each of the tablets of the potencies above is preferablyformulated in a 200 mg tablet containing 0.05 mL purified water USP pertablet.

[0079] The pharmaceutical tablet compositions of the present inventionmay also contain one or more additional formulation ingredients may beselected from a wide variety of excipients known in the pharmaceuticalformulation art. According to the desired properties of the tablet, anynumber of ingredients may be selected, alone or in combination, basedupon their known uses in preparing tablet compositions. Such ingredientsinclude, but are not limited to, diluents, compression aids,disintegrants, lubricants, flavors, flavor enhancers, sweetener andpreservatives. The pharmaceutical tablet compositions of the presentinvention do not, however, require the addition of a separate bindingexcipient because in wet granulation the active ingredient itself actsas a binding agent.

[0080] The term “tablet” as used herein is intended to encompasscompressed pharmaceutical dosage formulations of all shapes and sizes,whether coated or uncoated. Substances which may be used for coatinginclude hydroxypropylmethylcellulose, hydroxypropylcellulose, titaniumdioxide, talc, sweeteners, and colorants.

[0081] The pharmaceutical compositions of the present invention areuseful in the therapeutic or prophylactic treatment of disorders incalcium or phosphate metabolism and associated diseases. These diseasescan be divided into two categories:

[0082] 1. Abnormal (ectopic) depositions of calcium salts, mostlycalcium phosphate, pathological hardening of tissues and bonemalformations.

[0083] 2. Conditions which can benefit from a reduction in boneresorption. A reduction in bone resorption should improve the balancebetween resorption and formation, reduce bone loss or result in boneaugmentation. A reduction in bone resorption can alleviate the painassociated with osteolytic lesions and reduce the incidence and/orgrowth of those lesions.

[0084] These diseases include: osteoporosis (including estrogendeficiency, immobilization, glucocorticoid induced and senile),osteodystrophy, Paget's disease, myositis ossificans, Bechterew'sdisease, malignant hypercalcimia, metastatic bone disease, peridontaldisease, cholelithiasis, nephrolithiasis, urolithiasis, urinarycalculus, hardening of the arteries (sclerosis), arthritis, bursitis,neuritis and tetany.

[0085] Increased bone resorption can be accompanied by pathologicallyhigh calcium and phosphate concentrations in the plasma, which would bealleviated by use of the instant pharmaceutical compositions.

[0086] The following examples are given for the purpose of illustratingthe present invention and shall not be construed as being limitations onthe scope or spirit of the invention.

EXAMPLE 1 Procedure for Manufacturing 2.5 mg Potency Tablets of4-Amino-1-hydroxybutylidene-1,1-bisphosphonic acid

[0087] Per 10,000 Ingredients Per Tablet Tablets Active ingredient 3.26mg  32.6 g (monosodium salt trihydrate) Anhydrous Lactose, NF 113.74 mg 1137.4 g  Microcrystalline 80.0 mg 800.0 g Cellulose NF MagnesiumStearate 1.00 mg  10.0 g Impalpable Powder NF Croscarmellose Sodium 2.00mg  20.0 g NF Type A

[0088] The active ingredient (equivalent to 2.5 mg anhydrous free acidper tablet) was mixed with the microcrystalline cellulose NF and theanhydrous lactose NF in a high shear mixer for 3 minutes. Granulatingsolvent (550 mL water) was added to this blend with the mixer runningover a two minute period. The wetted mass was dried in a fluid bed dryerat an inlet temperature of 50° C. The dried material was then milledusing a FITZPATRICK J mill (hammer-type mill) to achieve fine granules.After milling, Croscarmellose Sodium NF type A (disintegrant) was addedto the blend and mixed in a ribbon blender for 5 minutes. MagnesiumStearate Impalpable Powder NF (lubricant) was added to this blendthrough a #60 mesh screen and blended for an additional 4 minutes. Thelubricated mixture was compressed to provide tablets of 2.5 mg activeingredient.

EXAMPLE 2 Procedure for Manufacturing 10 mg Potency Tablets of4-Amino-1-hydroxybutylidene-1,1-bisphosphonic acid

[0089] Per 10,000 Ingredients Per Tablet Tablets Active ingredient 13.05mg  130.5 g (monosodium salt trihydrate) Anhydrous Lactose, NF 103.95mg  1039.5 g  Microcrystalline 80.0 mg 800.0 g Cellulose NF MagnesiumStearate 1.00 mg  10.0 g Impalpable Powder NF Croscarmellose Sodium 2.00mg  20.0 g NF Type A

[0090] Tablets were prepared using essentially the procedure of Example1.

EXAMPLE 3 Procedure for Manufacturing 20 mg Potency Tablets of4-Amino-1-hydroxybutylidene-1,1-bisphosphonic acid

[0091] Per 10,000 Ingredients Per Tablet Tablets Active ingredient 26.11mg  261.1 g (monosodium salt trihydrate) Anhydrous Lactose, NF 90.89 mg 908.9 g Microcrystalline 80.0 mg 800.0 g Cellulose NF Magnesium Stearate 1.0 mg  10.0 g Impalpable Powder NF Croscarmellose Sodium  2.0 mg  20.0g NF Type A

[0092] Tablets were prepared using essentially the procedure of Example1.

[0093] While the foregoing specification teaches the principles of thepresent invention, with examples provided for the purpose ofillustration, it will be understood that the practice of the inventionencompasses all of the casual variations, adaptations, modifications,deletions, or additions of procedures and protocols described herein, ascome within the scope of the following claims and its equivalents.

What is claimed is:
 1. A process for the preparation of a tabletcontaining an active ingredient selected from the group consisting of:4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;N-methyl-4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;4-(N,N-dimethylamino)-1-hydroxybutylidene-1,1-bisphosphonic acid;3-amino-1-hydroxypropylidene-1,1-bis-phosphonic acid;3-(N,N-dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid;1-hydroxy-3-(N-methyl-N-pentylamino)propyl-idene-1,1-bisphosphonic acid;1-hydroxy-2-[3-pyridyl]ethylidene-1,1-bis-phosphonic acid; and4-(hydroxymethylene-1,1-bisphosphonic acid)-piperidine; or apharmaceutically acceptable salt thereof; which process comprises: (1)forming a powder blend of the active ingredient with diluents, (2) wetgranulating the powder blend with water to form granules, (3) drying thegranules to remove water, and (4) compressing the dried granules mixtureinto a desired tablet form.
 2. The process of claim 1 wherein the activeingredient is 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid.
 3. Theprocess of claim 1 wherein the active ingredient is4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium salttrihydrate.
 4. A process for the preparation of a tablet containing anactive ingredient selected from the group consisting of:4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;N-methyl-4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;4-(N,N-dimethylamino)-1-hydroxybutylidene-1,1-bisphosphonic acid;3-amino-1-hydroxypropylidene-1,1-bis-phosphonic acid;3-(N,N-dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid;1-hydroxy-3-(N-methyl-N-pentylamino)propyl-idene-1,1-bisphosphonic acid;1-hydroxy-2-[3-pyridyl]ethylidene-1,1-bis-phosphonic acid; and4-(hydroxymethylene-1,1-bisphosphonic acid)-piperidine; or apharmaceutically acceptable salt thereof; which process comprises: (1)forming a powder blend of the active ingredient with diluents from 3 to25 minutes using a mixer such as a planetary or high shear granulator,(2) wet granulating the powder blend by the addition of water whilemixing over a 2 to 30 minute period to form granules, (3) drying thegranules to remove water by the use of heated air for 10 minutes to 24hours, (4) milling the dried granules to a uniform size, (5) adding andblending a disintegrant with the dried milled particles for 2 to 30minutes, (6) adding and blending a lubricant to the mixture containingthe disintegrant for 30 seconds to 20 minutes, and (7) compressing thedried granules mixture into a desired tablet form.
 5. The process ofclaim 4 wherein the active ingredient is4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid.
 6. The process ofclaim 4 wherein the active ingredient is4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium salttrihydrate.
 7. The process of claim 4 wherein the diluents are selectedfrom: lactose, microcrystalline cellulose, calcium phosphate, mannitol,powdered cellulose, and pregelatinized starch.
 8. The process of claim 7wherein the diluents are lactose and microcrystalline cellulose.
 9. Theprocess of claim 8 wherein the lactose is lactose NF anhydrous and themicrocrystalline cellulose is Avicel PH101.
 10. The process of claim 4wherein the disintegrant is selected from the group consisting ofmodified starch, modified cellulose polymer, and croscarmellose sodium,or a combination thereof.
 11. The process of claim 10 wherein thedisintegrant is croscarmellose sodium.
 12. The process of claim 11wherein the disintegrant is croscarmellose sodium NF type A.
 13. Theprocess of claim 4 wherein the lubricant is selected from the groupconsisting of magnesium stearate, calcium stearate, stearic acid, sodiumlauryl sulfate, propylene glycol, sodium dodecane sulfonate, sodiumoleate sulfonate, sodium laurate mixed with stearates and talc, andsodium stearyl fumerate.
 14. The process of claim 13 wherein thelubricant is magnesium stearate.
 15. The process of claim 4 whichcomprises the steps: (1) forming a powder blend of4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, microcrystallinecellulose, and lactose with a high shear granulator for 3 to 5 minutes,(2) wet granulating the powder blend by the addition of water whilemixing over a 3 to 5 minute period to form granules with the high sheargranulator, (3) drying the granules to remove water by the use of heatedair by drying 10 minutes to 1 hour with a Fluid bed, or 12 to 24 hoursin a tray dryer, (4) milling the dried granules to a uniform size usinga hammer type mill, (5) adding and blending the disintegrantcroscarmellose sodium NF type A with the dried milled particles for 3 to8 minutes, (6) adding and blending magnesium stearate lubricant to themixture containing the croscarmellose sodium NF type A disintegrant witha ribbon blender or a planetary mixer for 3 to 8 minutes, (7)compressing the lubricated granule mixture into a desired tablet form,and (8) dedusting and storing the tablets.
 16. The process of claim 4which comprises the steps: (1) forming a powder blend of4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, microcrystallinecellulose, and lactose with a planetary granulator for 10 to 25 minutes,(2) wet granulating the powder blend by the addition of water whilemixing over a 3 to 10 minute period to form granules with the planetarygranulator, (3) drying the granules to remove water by the use of heatedair by drying 10 minutes to 1 hour with a fluid bed, or 12-24 hours in atray dryer, (4) milling the dried granules to a uniform size using ahammer type mill, (5) adding and blending the disintegrantcroscarmellose sodium NF type A with the dried milled particles for 3 to8 minutes, (6) adding and blending magnesium stearate lubricant to themixture containing the croscarmellose sodium NF type A disintegrant witha ribbon blender or a planetary granulator for 3 to 8 minutes, and (7)compressing the lubricated granule mixture into a desired tablet form,and (8) dedusting and storing the tablets.
 17. The process of claim 4which comprises the steps: (1) forming a powder blend of4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, Avicel PH101microcrystalline cellulose, and lactose with a high shear granulator for3 to 5 minutes, (2) wet granulating the powder blend by the addition ofwater while mixing over a 3 to 5 minute period to form granules with ahigh shear granulator, (3) drying the granules to remove water by theuse of heated air for 10 minutes to one hour using a fluid bed dryer,(4) milling the dried granules to a uniform size using a hammer typemill, (5) adding and blending the disintegrant croscarmellose sodium NFtype A with the dried milled particles for 3 to 8 minutes, (6) addingand blending magnesium stearate lubricant to the mixture containing thecroscarmellose sodium NF type A disintegrant with a ribbon blender for 3to 8 minutes, (7) compressing the lubricated granule mixture into adesired tablet form, and (8) dedusting and storing the tablets.
 18. Asolid dosage form containing an active ingredient selected from thegroup consisting of: 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;N-methyl-4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;4-(N,N-dimethylamino)-1-hydroxybutylidene-1,1-bisphosphonic acid;3-amino-1-hydroxypropylidene-1,1-bis-phosphonic acid;3-(N,N-dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid;1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid;1-hydroxy-2-[3-pyridyl]ethylidene-1,1-bis-phosphonic acid; and4-(hydroxymethylene-1,1-bisphosphonic acid)-piperidine; or apharmaceutically acceptable salt thereof; wherein the dosage form isprepared by the process of claim
 1. 19. A pharmaceutical compositioncomprising by weight, about 0.5 to 25% by weight of an active ingredientselected from the group consisting of:4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;N-methyl-4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;4-(N,N-dimethylamino)-1-hydroxybutylidene-1,1-bisphosphonic acid;3-amino-1-hydroxypropylidene-1,1-bis-phosphonic acid;3-(N,N-dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid;1-hydroxy-3-(N-methyl-N-pentylamino)propyl-idene-1,1-bisphosphonic acid;1-hydroxy-2-[3-pyridyl]ethylidene-1,1-bis-phosphonic acid; and4-(hydroxymethylene-1,1-bisphosphonic acid)-piperidine; or apharmaceutically acceptable salt thereof; and from about 30 to 70% byweight of anhydrous lactose or hydrous fast flow lactose; about 30 to50% by weight of microcrystalline cellulose, and about 0.1 to 2% byweight magnesium stearate.
 20. The pharmaceutical composition of claim19 comprising about 1 to 25% by weight of the active ingredient, about40 to 60% by weight of anhydrous lactose; about 35 to 45% by weight ofmicrocrystalline cellulose; about 0.5 to 2% by weight croscarmellosesodium and about 0.1 to 1% by weight of magnesium stearate.
 21. Thepharmaceutical composition of claim 18 wherein the active ingredient is4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid.
 22. Thepharmaceutical composition of claim 18 wherein the active ingredient is4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium salttrihydrate.
 23. The pharmaceutical composition of claim 20 wherein theactive ingredient is 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acidmonosodium salt trihydrate. 24 A tablet prepared from the pharmaceuticalcomposition of claim
 23. 25. A tablet prepared from the pharmaceuticalcomposition of claim 18.